Reversal of Experimental Autoimmune Diabetes With an sCD39/Anti-CD3 Treatment.

Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes. We then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NOD mice compared with prediabetic NOD mice. CD39 and CD73 were found expressed by both α- and ß-cells and by different subsets of T cells. Importantly, prediabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pancreatic lymph nodes, and spleens. The administration of sCD39 into prediabetic NOD mice reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T cells, and increased the frequency of regulatory T cells, while delaying the onset of T1D. Notably, concomitant administration of sCD39 and anti-CD3 showed a strong synergism in restoring normoglycemia in newly hyperglycemic NOD mice compared with monotherapy with anti-CD3 or with sCD39. The eATP/CD39 pathway plays an important role in the onset of T1D, and its targeting might represent a potential therapeutic strategy in T1D.

The nature and characteristics of hypertriglyceridemia in a large cohort with type 2 diabetes.

AIMS: To determine the prevalence of mild, moderate and severe hypertriglyceridemia (HTG) in a large, diverse healthcare system cohort with type 2 diabetes (T2D) and to study associations between triglyceride levels and demographic factors, glycemic control, body weight and to investigate whether triglyceride levels associate with markers of fatty liver and renal disease. METHODS: 19,086 individuals with T2D were studied between 2015 and 2020. We compared groups with normotriglyceridemia (<150 mg/dl [<1.7 mmol/l]), mild (150-199 mg/dl [1.7-2.25 mmol/l]), moderate (200-499 mg/dl [2.26-5.64 mmol/l]) or severe HTG (>499 mg/dl [>5.64 mmol/l]). We also performed univariate and multivariate correlational analyses with triglyceride level as a continuous variable. RESULTS: 39 % had triglyceride levels ≥150 mg/dl (<1.7 mmol/l), 19 % had moderate and 2 % had severe HTG. There was a lower proportion of Blacks in all HTG categories compared to Whites. There was no overall gender difference in prevalence except that severe HTG was more common in men and as HTG severity worsened mean age fell. Triglycerides correlated with HbA1c and associated with BMI, LDL-C, diastolic BP, transaminases and urine albumin/creatinine ratio, independent of HbA1c. CONCLUSION: This study fills gaps in our knowledge of the distribution and clinical associations of HTG in T2D and characterizes the features of the small but important group with severe HTG. We demonstrate the influence of age, sex and race, confirm the moderate effects of glycemic control and obesity on triglyceride level, and provide evidence that triglyceride levels may be a marker for fatty liver and nephropathy independent of glycemic control.

Advances in human oxytocin measurement: challenges and proposed solutions.

Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies-including the design and study of hormone secretion and biochemical assays-present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies.

Characterization of Gastrointestinal Hormone Dysfunction and Metabolic Pathophysiology in Experimental Spinal Cord Injury.

Cardiometabolic disease is a leading complication of spinal cord injury (SCI) that contributes to premature all-cause cardiovascular morbidity and early death. Despite widespread reports that cardioendocrine disorders are more prevalent in individuals with SCI than those without disability, a well-defined pathophysiology has not been established. Autonomic dysfunction accompanying disruption of autonomic spinal tracts may contribute to dysregulation of energy metabolism via uncoupling of integrated hunger and satiation signals. In governing human feeding behaviors, these signals are controlled by a network of enteroendocrine cells that line the gastrointestinal (GI) tract. These cells regulate GI peptide release and autonomic systems that maintain direct neuroendocrine communication between the GI tract and appetite circuitry of the hypothalamus and brainstem. Here we investigate gene-expression and physiological changes in GI peptides and hormones, as well as changes in physiological response to feeding, glucose and insulin challenge, and evaluate GI tissue cytoarchitecture after experimental SCI. Adult female mice (C57BL/6) were subjected to a severe SCI (65 kDyne) at T9, and a sham control group received laminectomy only. The SCI results in chronic elevation of fasting plasma glucose levels and an exaggerated glucose response after an oral glucose and insulin tolerance test. Mice with SCI also exhibit significant alteration in gut hormone genes, plasma levels, physiological response to prandial challenge, and cell loss and gross tissue damage in the gut. These findings demonstrate that SCI has widespread effects on the GI system contributing to component cardiometabolic disease risk factors and may inform future therapeutic and rehabilitation strategies in humans.

Oxytocin reactivity to a lab-based stressor predicts support seeking after stress in daily life: Implications for the Tend-and-Befriend theory.

Social relationships play an important role in mental and physical health, particularly during times of stress. However, little is known about the biological mechanisms underlying the tendency to seek support following stress. The Tend-and-Befriend theory suggests that oxytocin (OT) may enhance the desire for social contact in response to stress. Yet, no studies in humans have provided empirical support for the connection between stress-induced changes in endogenous OT and increased support seeking after stress. In the present study, 94 participants performed a standardized laboratory stressor and then completed two weeks of daily assessments of support seeking after stress. In line with preregistered hypotheses, stress-induced plasma OT reactivity to the laboratory stressor was associated with more frequent support seeking behaviors following stress in daily life (i.e., outside of the laboratory). Additional results suggested that attachment anxiety (but not avoidance) strengthened this association. Our findings implicate the OT system in affiliative behaviors following stress, providing empirical support for the Tend-and-Befriend theory.

Social anxiety is associated with greater peripheral oxytocin reactivity to psychosocial stress.

To date, it has been difficult to establish reliable biomarkers associated with specific forms of psychopathology. Social anxiety, for example, is associated with inconsistent biological responses to psychosocial stress on markers including cortisol and salivary alpha-amylase. Thus, it is critical that studies identify more reliable biomarkers that index patterns associated with social anxiety. Two potential candidates are the neuropeptides oxytocin and vasopressin, which have been implicated in stress responsivity across species. Studies have demonstrated a reliable increase in oxytocin, and a surrogate marker for vasopressin, following engagement in the most widely used lab-based psychosocial stress paradigm: the Trier Social Stress Test (TSST). However, no study has examined whether social anxiety moderates peripheral oxytocin or vasopressin reactivity to psychosocial stress. In 101 young adult participants, dimensionally assessed social anxiety was associated with greater plasma oxytocin, but not vasopressin, reactivity to the TSST. Results were maintained following the inclusion of depression as a covariate. Findings suggest that studying changes in peripheral oxytocin concentrations may be a method of differentiating individuals with higher levels of social anxiety.

Physical touch during father-infant interactions is associated with paternal oxytocin levels.

INTRODUCTION: Physical connection, particularly parent-to-infant touch, is critical for the well-being of infants and may support the development of the parent-infant bond. Physical touch has also been found to stimulate oxytocin levels. This study tested whether fathers' micro-coded touch behaviors during parent-child interaction predicted their subsequent oxytocin levels. We also compared two widely-used methods of oxytocin immunoassay that have been found to yield discrepant results in past studies. METHODS: Among 45 fathers and their six-month-old infants, we micro-coded paternal physical touch at 1/10 s intervals during a laboratory-based free-play interaction. Paternal oxytocin was measured via blood plasma and was processed both with and without the extraction step prior to immunoassay so that results from the two methods could be compared. RESULTS: Unextracted and extracted oxytocin were moderately correlated within our sample. Fathers who engaged in more playful proprioceptive touch showed higher levels of both unextracted and extracted oxytocin. Gentle affectionate touch and functional proprioceptive touch predicted higher unextracted but not extracted oxytocin levels. Fathers who did not engage in physical touch showed lower levels of both unextracted and extracted oxytocin. CONCLUSION: Results are consistent with previous work showing that physical touch, particularly playful proprioceptive touch, is associated with higher oxytocin levels in fathers. These results replicate previous research using unextracted oxytocin measurement, and extend this work, showing that many but not all associations hold when using the more rigorous method of extraction when measuring oxytocin.

Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment.

OBJECTIVE: Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine and cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and antitumor processes in ovarian cancer. METHODS: Patients with ovarian cancer (n = 96) completed assessments of positive psychosocial factors (social support, positive affect, and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and interleukin (IL) 6 in ascites fluid were obtained during surgery and analyzed by enzyme-linked immunosorbent assay. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships. RESULTS: Higher levels of positive affect (ß = 0.22, p = .034), purpose in life (ß = 0.31, p = .021), and social nurturance (ß = 0.24, p = .024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life, and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model. CONCLUSIONS: Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study.

Cardiometabolic risks and atherosclerotic disease in ApoE knockout mice: Effect of spinal cord injury and Salsalate anti-inflammatory pharmacotherapy.

OBJECTIVE: To test in mice with a double mutation of the ApoE gene (ApoE-/-) whether spinal cord injury (SCI) hastens the native trajectory of, and established component risks for, atherosclerotic disease (AD), and whether Salsalate anti-inflammatory pharmacotherapy attenuates the impact of SCI. METHODS: ApoE-/- mice were anesthetized and underwent a T9 laminectomy. Exposed spinal cords were given a contusion injury (70 k-dynes). Sham animals underwent all surgical procedures, excluding injury. Injured animals were randomized to 2 groups: SCI or SCI+Salsalate [120 mg/Kg/day i.p.]. Mice were serially sacrificed at 20-, 24-, and 28-weeks post-SCI, and body mass was recorded. At sacrifice, heart and aorta were harvested intact, fixed in 10% buffered formalin, cleaned and cut longitudinally for en face preparation. The aortic tree was stained with oil-red-O (ORO). AD lesion histomorphometry was calculated from the proportional area of ORO. Plasma total cholesterol, triglycerides and proatherogenic inflammatory cytokines (PAIC's) were analyzed. RESULTS: AD lesion in the aortic arch progressively increased in ApoE-/-, significant at 24- and 28-weeks. AD in SCI is significantly greater at 24- and 28-weeks compared to time-controlled ApoE-/-. Salsalate treatment attenuates the SCI-induced increase at these time points. Body mass in all SCI groups are significantly reduced compared to time-controlled ApoE-/-. Cholesterol and triglycerides are significantly higher with SCI by 24- and 28-weeks, compared to ApoE-/-, and Salsalate reduces the SCI-induced effect on cholesterol. PAIC's interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-C motif) ligand 5 (CCL-5) are significantly greater with SCI compared to ApoE-/- at varying timepoints. Salsalate confers a marginal reducing effect on PAIC's by 28-weeks compared to SCI. Regression models determine that each PAIC is a significant and positive predictor of lesion. (p's <0.05). CONCLUSIONS: SCI accelerates aortic AD and associated risk factors, and anti-inflammatory treatment may attenuate the impact of SCI on AD outcomes. PAIC's IL-1ß, IL-6, TNFα, MCP-1, and CCL-5 may be effective predictors of AD.

Effects of Exercise Mode on Postprandial Metabolism in Humans with Chronic Paraplegia.

PURPOSE: The purpose of this study was to assess the acute effects of exercise mode and intensity on postprandial macronutrient metabolism. METHODS: Ten healthy men age 39 ± 10 yr with chronic paraplegia (13.2 ± 8.8 yr, ASIA A-C) completed three isocaloric bouts of upper-body exercise and a resting control. After an overnight fast, participants completed circuit resistance exercise (CRE) first and the following conditions in a randomized order, separated by >48 h: i) control (CON), ~45-min seated rest; ii) moderate-intensity continuous exercise (MICE), ~40-min arm cranking at a resistance equivalent to ~30% peak power output (PPO); and iii) high-intensity interval exercise (HIIE), ~30 min arm cranking with resistance alternating every 2 min between 10% PPO and 70% PPO. After each condition, participants completed a mixed-meal tolerance test consisting of a 2510-kJ liquid meal (35% fat, 50% carbohydrate, 15% protein). Blood and expired gas samples were collected at baseline and regular intervals for 150 min after a meal. RESULTS: An interaction (P < 0.001) was observed, with rates of lipid oxidation elevated above CON in HIIE until 60 min after a meal and in CRE at all postprandial time points up to 150 min after a meal. Postprandial blood glycerol was greater in MICE (P = 0.020) and CRE (P = 0.001) compared with CON. Furthermore, nonesterified fatty acid area under the curve had a moderate-to-strong effect in CRE versus MICE and HIIE (Cohen's d = -0.76 and -0.50, respectively). CONCLUSIONS: In persons with paraplegia, high-intensity exercise increased postprandial energy expenditure independent of the energy cost of exercise. Furthermore, exercise combining resistance and endurance modes (CRE) showed the greater effect on postprandial lipid oxidation.

APOL1 risk variants affect podocyte lipid homeostasis and energy production in focal segmental glomerulosclerosis.

Lipotoxicity was recently reported in several forms of kidney disease, including focal segmental glomerulosclerosis (FSGS). Susceptibility to FSGS in African Americans is associated with the presence of genetic variants of the Apolipoprotein L1 gene (APOL1) named G1 and G2. If and how endogenous APOL1 may alter mitochondrial function by the modifying cellular lipid metabolism is unknown. Using transgenic mice expressing the APOL1 variants (G0, G1 or G2) under endogenous promoter, we show that APOL1 risk variant expression in transgenic mice does not impair kidney function at baseline. However, APOL1 G1 expression worsens proteinuria and kidney function in mice characterized by the podocyte inducible expression of nuclear factor of activated T-cells (NFAT), which we have found to cause FSGS. APOL1 G1 expression in this FSGS-model also results in increased triglyceride and cholesterol ester contents in kidney cortices, where lipid accumulation correlated with loss of renal function. In vitro, we show that the expression of endogenous APOL1 G1/G2 in human urinary podocytes is associated with increased cellular triglyceride content and is accompanied by mitochondrial dysfunction in the presence of compensatory oxidative phosphorylation (OXPHOS) complexes elevation. Our findings indicate that APOL1 risk variant expression increases the susceptibility to lipid-dependent podocyte injury, ultimately leading to mitochondrial dysfunction.

Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.

BACKGROUND: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is activated by collagens that is involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production of the collagen type I (Col I) has been observed in Col4a3 knockout mice, a mouse model of Alport Syndrome (AS mice). Deletion of the DDR1 in AS mice was shown to improve survival and renal function. However, the mechanisms driving DDR1-dependent fibrosis remain largely unknown. METHODS: Podocyte pDDR1 levels, Collagen and cluster of differentiation 36 (CD36) expression was analyzed by Real-time PCR and Western blot. Lipid droplet accumulation and content was determined using Bodipy staining and enzymatic analysis. CD36 and DDR1 interaction was determined by co-immunoprecipitation. Creatinine, BUN, albuminuria, lipid content, and histological and morphological assessment of kidneys harvested from AS mice treated with Ezetimibe and/or Ramipril or vehicle was performed. FINDINGS: We demonstrate that Col I-mediated DDR1 activation induces CD36-mediated podocyte lipotoxic injury. We show that Ezetimibe interferes with the CD36/DDR1 interaction in vitro and prevents lipotoxicity in AS mice thus preserving renal function similarly to ramipril. INTERPRETATION: Our study suggests that Col I/DDR1-mediated lipotoxicity contributes to renal failure in AS and that targeting this pathway may represent a new therapeutic strategy for patients with AS and with chronic kidney diseases (CKD) associated with Col4 mutations. FUNDING: This study is supported by the NIH grants R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460 (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities), F32DK115109, Hoffmann-La Roche and Alport Syndrome Foundation.

Maternal anemia and preterm birth among women living with HIV in the United States.

BACKGROUND: Women living with HIV (WLHIV) have a higher prevalence of anemia than women without HIV, possibly related to the effects of HIV and antiretroviral medications. OBJECTIVES: To estimate the prevalence of anemia in the third trimester of pregnancy and the effect of anemia on preterm births in WLHIV in the longitudinal, US-based Pediatric HIV/AIDS Cohort Study (PHACS). METHODS: During the third trimester, we obtained up to three 24-hour dietary recalls to estimate daily intakes of nutrients and measured serum concentrations of iron, vitamin B6, vitamin B12, zinc, folate, ferritin, total iron-binding capacity (TIBC), and high sensitivity C-reactive protein. Third trimester anemia was defined as hemoglobin < 11 g/d and iron-deficiency anemia (IDA) was defined as low ferritin, high TIBC, and low transferrin saturation. A preterm birth was defined as birth at < 37 completed weeks of gestation, regardless of etiology. We fit separate modified Poisson regression models for each outcome (anemia, preterm birth) and each main exposure, adjusted for confounders, and report adjusted prevalence ratios (aPR) and 95% CIs. RESULTS: Of the 267 WLHIV, 50% were anemic in the third trimester, of whom 43.5% (n = 57/131) had IDA. On average, women with anemia were younger, were more likely to be black, started antiretroviral medications in the second trimester, had a low CD4 count (<200 cells/mm3) early in pregnancy, and were less likely to meet recommended intakes for iron, B6, and folate. The prevalence of anemia was greater in WLHIV with a low CD4 count (aPR = 1.65; 95% CI: 1.20-2.27) and high HIV viral load (>10,000 copies/mL; aPR = 1.38; 95% CI: 1.02-1.87). In total, 16% of women delivered preterm. Anemia was associated with a 2-fold (aPR = 2.04; 95% CI: 1.12-3.71) higher prevalence of preterm births. CONCLUSIONS: Anemia is common in pregnant WLHIV, highlighting the need to address the underlying factors and clinical outcomes of anemia in this population.

Roles of age and sources of cancer caregiving stress in self-reported health and neuroendocrine biomarkers.

OBJECTIVE: To investigate the extent to which age and specific sources of caregiving stress are associated with cancer caregivers' health. Methods: New colorectal cancer caregivers (n = 88; age M = 49) reported caregiving stress (i.e., disrupted schedule, lacking family support, financial strain) and mental and physical health, and collected saliva samples assayed for neuroendocrine biomarkers (cortisol and α-amylase). Results: Disrupted daily schedule due to caregiving was associated with poorer self-reported mental health across all ages (B= -4.19, 95% CI: -6.59--1.80, p <.01), and associated with dysregulated cortisol patterns among older caregivers, but with more regulated cortisol patterns among younger caregivers, ps ≤ .01. Across all ages, lacking family support was associated with poorer self-reported physical health (B= -2.13, 95% CI: -4.33--0.07, p <.05), but more regulated α-amylase patterns (B = 2.51, 95% CI: 0.83-4.19, p <.01). Financial strain related to regulated cortisol levels only among older caregivers (B = 5.07, 95% CI: 0.58-9.57, p = .03) and more regulated α-amylase patterns across all ages (B= -25.81, 95% CI: -48.72--2.90, p <.05). Conclusion: Findings suggest that specific sources of caregiver stress manifest in health outcomes distinctly by age, and support the need for targeted psychosocial interventions for cancer caregivers.

Osteopontin and LDLR Are Upregulated in Hearts of Sudden Cardiac Death Victims With Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus.

Background: Diabetes mellitus (DM) is associated with increased risk of sudden cardiac death (SCD), particularly in patients with heart failure with preserved ejection fraction (HFpEF). However, there are no known biomarkers in the population with DM and HFpEF to predict SCD risk. Objectives: This study was designed to test the hypothesis that osteopontin (OPN) and some proteins previously correlated with OPN, low-density lipoprotein receptor (LDLR), dynamin 2 (DNM2), fibronectin-1 (FN1), and 2-oxoglutarate dehydrogenase-like (OGDHL), are potential risk markers for SCD, and may reflect modifiable molecular pathways in patients with DM and HFpEF. Methods: Heart tissues were obtained at autopsy from 9 SCD victims with DM and HFpEF and 10 age and gender-matched accidental death control subjects from a Finnish SCD registry and analyzed for the expression of OPN and correlated proteins, including LDLR, DNM2, FN1, and OGDHL by immunohistochemistry. Results: We observed a significant upregulation in the expression of OPN, LDLR, and FN1, and a marked downregulation of DNM2 in heart tissues of SCD victims with DM and HFpEF as compared to control subjects (p < 0.01). Conclusions: The dysregulated protein expression of OPN, LDLR, FN1, and DNM2 in patients with DM and HFpEF who experienced SCD provides novel potential modifiable molecular pathways that may be implicated in the pathogenesis of SCD in these patients. Since secreted OPN and soluble LDLR can be measured in plasma, these results support the value of further prospective studies to assess the predictive value of these plasma biomarkers and to determine whether tuning expression levels of OPN and LDLR alters SCD risk in patients with DM and HFpEF.

Oxytocin reduces adipose tissue inflammation in obese mice.

BACKGROUND: Obesity and adipose tissue expansion is characterized by a chronic state of systemic inflammation that contributes to disease. The neuropeptide, oxytocin, working through its receptor has been shown to attenuate inflammation in sepsis, wound healing, and cardiovascular disease. The current study examined the effects of chronic oxytocin infusions on adipose tissue inflammation in a murine model of obesity, the leptin receptor-deficient (db/db) mouse. METHODS: The effect of obesity on oxytocin receptor protein and mRNA expression in adipose tissue was evaluated by Western blotting and real-time polymerase chain reaction. Mice were implanted with osmotic minipumps filled with oxytocin or vehicle for 8 weeks. At study endpoint adipose tissue inflammation was assessed by measurement of cytokine and adipokine mRNA tissue levels, adipocyte size and macrophage infiltration via histopathology, and plasma levels of adiponectin and serum amyloid A as markers of systemic inflammation. RESULTS: The expression of adipose tissue oxytocin receptor was increased in obese db/db mice compared to lean controls. In adipose tissue oxytocin infusion reduced adipocyte size, macrophage infiltration, IL-6 and TNFα mRNA expression, and increased the expression of the anti-inflammatory adipokine, adiponectin. In plasma, oxytocin infusion reduced the level of serum amyloid A, a marker of systemic inflammation, and increased circulating adiponectin. CONCLUSIONS: In an animal model of obesity and diabetes chronic oxytocin treatment led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which may play a role in disease progression.

Serum copper profile in patients with type 1 diabetes in comparison to other metals.

BACKGROUND: Type 1 diabetes (T1D) is a chronic condition in which the pancreas loses the ability to produce insulin due to an autoimmune destruction of the insulin producing beta cells in the pancreatic islets of Langerhans. Pathophysiological complications related to diabetes include micro and macrovascular disease, nephropathy, and neuropathy that can also be affected by environmental factors such as lifestyle and diet. OBJECTIVES: The current study aimed to evaluate the serum levels of total copper, the copper-carrying protein, ceruloplasmin and nonceruloplasmin bound copper (nonceruloplasmin-Cu) and other essential and environmental metals and metalloids in subjects with T1D compared with healthy controls. METHODS: A cohort of 63 subjects with T1D attending Diabetes Clinics at the University of Miami and 65 healthy control subjects was studied. Metals and metalloids were measured by inductively coupled plasma mass spectrometry. RESULTS: A main finding of this study was that total copper and ceruloplasmin levels were higher in persons with T1D compared to healthy controls. In comparison to other metals and clinical variables, elevated copper was the strongest factor associated with T1D resulting in a15-fold increased odds of having the disease per standard deviation increase. CONCLUSION: Our results suggest a metal and metalloid perturbation in T1D with a significant involvement of Copper dysfunction in the disease pathology, possibly linked to inflammatory processes.

Influence of upper-body continuous, resistance or high-intensity interval training (CRIT) on postprandial responses in persons with spinal cord injury: study protocol for a randomised controlled trial.

BACKGROUND: Chronic spinal cord injury (SCI) increases morbidity and mortality associated with cardiometabolic diseases, secondary to increases in central adiposity, hyperlipidaemia and impaired glucose tolerance. While upper-body Moderate Intensity Continuous Training (MICT) improves cardiorespiratory fitness, its effects on cardiometabolic component risks in adults with SCI appear relatively modest. The aim of this study is to assess the acute effects of Continuous Resistance Training (CRT), High Intensity Interval Training (HIIT), MICT and rest (CON) on fasting and postprandial systemic biomarkers and substrate utilisation. METHODS: Eleven healthy, chronic SCI (> 1 year, ASIA A-C) men will be recruited. Following preliminary testing, each will complete four experimental conditions, where they will report to the laboratory following an ~ 10-h overnight fast. A venous blood sample will be drawn and expired gases collected to estimate resting metabolic rate (RMR). In order to ensure an isocaloric exercise challenge, each will complete CRT first, with the remaining three conditions presented in randomised order: (1) CRT, ~ 45 min of resistance manoeuvres (weight lifting) interspersed with low-resistance, high-speed arm-crank exercise; (2) CON, seated rest; (3) MICT, ~ 45 min constant arm-crank exercise at a resistance equivalent to 30-40% peak power output (PPO) and; (4) HIIT, ~ 35 min arm-crank exercise with the resistance alternating every 2 min between 10% PPO and 70% PPO. After each ~ 45-min condition, participants will ingest a 2510-kJ liquid test meal (35% fat, 50% carbohydrate, 15% protein). Venous blood and expired gas samples will be collected at the end of exercise and at regular intervals for 120 min post meal. DISCUSSION: This study should establish the acute effects of different forms of exercise on fasting and postprandial responses in chronic SCI male patients. Measures of glucose clearance, insulin sensitivity, lipid and inflammatory biomarker concentrations will be assessed and changes in whole-body substrate oxidation estimated from expired gases. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03545867 . Retrospectively registered on 1 June 2018.

ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes.

Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1fl/fl) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1fl/fl mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.

Third Trimester Vitamin D Status Is Associated With Birth Outcomes and Linear Growth of HIV-Exposed Uninfected Infants in the United States.

BACKGROUND: Vitamin D status in pregnancy may influence the risk of prematurity, birth size, and child postnatal growth, but few studies have examined the relationship among pregnant women living with HIV. METHODS: We conducted a prospective cohort study of 257 HIV-infected mothers and their HIV-exposed uninfected infants who were enrolled in the 2009-2011 nutrition substudy of the Surveillance Monitoring for ART Toxicities (SMARTT) study. HIV-infected pregnant women had serum 25-hydroxyvitamin D (25(OH)D) assessed in the third trimester of pregnancy, and their infants' growth and neurodevelopment were evaluated at birth and approximately 1 year of age. RESULTS: The mean third trimester serum 25(OH)D concentration was 35.4 ± 14.2 ng/mL with 15% of women classified as vitamin D deficient (<20 ng/mL) and 21% as insufficient (20-30 ng/mL). In multivariable models, third trimester vitamin D deficiency and insufficiency were associated with -273 g [95% confidence interval (CI): -450 to -97] and -203 g (95% CI: -370 to -35) lower birth weights compared with vitamin D sufficient women, respectively. Maternal vitamin D deficiency was also associated with shorter gestation (mean difference -0.65 weeks; 95% CI: -1.22 to -0.08) and lower infant length-for-age z-scores at 1 year of age (mean difference: -0.65; 95% CI: -1.18 to -0.13). We found no association of vitamin D status with infant neurodevelopment at 1 year of age. CONCLUSION: Third trimester maternal vitamin D deficiency was associated with lower birth weight, shorter length of gestation, and reduced infant linear growth. Studies and trials of vitamin D supplementation in pregnancy for women living with HIV are warranted.